1. Field of the Invention
This invention relates to an improved method for conducting scintigraphy to monitor immunotoxins under clinical conditions. The improvement relates to the use of heterobifunctional chelators to bind radionuclides exclusively to the cytotoxic moiety of an immunotoxin.
2. Information Disclosure
The localization of radiolabelled monoclonal antibodies in tumours has been described (Halpern, S.E., Et Al: Stability, Characterization and Kinetics of .sup.111 In-labelled monoclonal antitumor antibodies in normal animals and nude mouse-human tumor models. Cancer Res., 43, 5355, 1983). Using radiolabels appropriate for gamma camera imaging, such as radioiodines (.sup.131 I or 123I) or radiometals (.sup.111 In or .sup.99m Tc), monoclonal antibodies have been evaluated for imaging primary and recurrent malignant disease (Reviewed in Pimm, M.V. Immunoscintigraph: Tumour detection with radiolabelled antitumour antibodies. In: Immunology of Malignant Diseases. (eds) V.S. Byers and R.W. Baldwin, MTP Press Ltd., Lancaster, pp 21-43, 1987).
The scintigraphic expertise developed with radiolabelled antibodies can be used to examine the biodistribution of immunoconjugates; however, to date there has been little work in this field. Ford, et al., (Localization and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. Br. J. Cancer, 47, 35-42, 1983) imaged the biodistribution and tumour localization of .sup.131 I-I-labelled vindesine-antiCEA polyclonal antibody conjugate. Perkins, et al., (In vivo imaging of a monoclonal antibody drug conjugate (791T/36-Methotrexate): Experimental and Clinical Studies. In: Fourth Hamburg Symposium uber Tumormarker. (eds) H. Greten and R. Klapden, Georg Thieme Verlag Stuttgart, pp 559-562, 1988) carried out similar studies with a .sup.131 I-labelled monoclonal antibody-methotrexate conjugate in patients with colorectal cancer. These procedures have, however, only imaged the distribution of the antibody part of the conjugate without formal proof that the distribution of the drug paralleled that of the antibody. Direct observation of drug distribution has been limited by the difficulty in radiolabelling drugs with sufficient specific activity to permit external detection.
In the case of conjugates of antibody with protein toxins such as ricin toxin A chain (RTA) it is feasible to prepare conjugates in which either the whole molecule, or only the RTA or antibody moieties are radiolabelled, or even in which each component is independently labelled with a different radionuclide (Byers, et al., Biodistribution of ricin toxin A chain monoclonal antibody 791T/36 immunotoxin and the influence of hepatic blocking agents. Cancer Res., 47, 5277-5282, 1987). Preliminary studies on the imaging of the biodistribution in mice of RTA-monoclonal antibody 791T/36 conjugates in which only the RTA was labelled with .sup.131 I have also been reported. (Perkins, et al. Demonstration of the hepatic uptake of radiolabelled immunotoxins using gamma scintigraphy. Eur. J. Cancer Clin. Oncol., 23, 1225-1227, 1987).